Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review

Abstract

Objective To characterize the prospective controlled clinical studies for all novel drugs that were initially approved by the Food and Drug Administration on the basis of limited evidence. Design Systematic review. Data sources Drugs@FDA database and PubMed. Study inclusion All prospective controlled clinical studies published after approval for all novel drugs initially approved by the FDA between 2005 and 2012 on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease as primary endpoints, or both. Results Between 2005 and 2012 the FDA approved 117 novel drugs for 123 indications on the basis of a single pivotal trial, pivotal trials that used surrogate markers of disease, or both (single surrogate trials). We identified 758 published controlled studies over a median of 5.5 years (interquartile range 3.4-8.2) after approval, most of which (554 of 758; 73.1%) were studies for indications approved on the basis of surrogate markers of disease. Most postapproval studies used active comparators—67 of 77 (87.0%) indications approved on the basis of single pivotal trials, 365 of 554 (65.9%) approvals based on surrogate marker trials, and 100 of 127 (78.7%) approvals based on single surrogate trials—and examined surrogate markers of efficacy as primary endpoints—51 of 77 (66.2%), 512 of 554 (92.4%), and 110 of 127 (86.6%), respectively. Overall, no postapproval studies were identified for 43 of the 123 (35.0%) approved indications. The median total number of postapproval studies identified was 1 (interquartile range 0-2) for indications approved on the basis of a single pivotal trial, 3 (1-8) for indications approved on the basis of pivotal trials that used surrogate markers of disease as primary endpoints, and 1 (0-2) for single surrogate trial approvals, and the median aggregate number of patients enrolled in postapproval studies was 90 (0-509), 533 (122-3633), and 38 (0-666), respectively. The proportion of approved indications with one or more randomized, controlled, double blind study using a clinical outcome for the primary endpoint that was published after approval and showed superior efficacy was 18.2% (6 of 33), 2.0% (1 of 49), and 4.9% (2 of 41), respectively. Conclusions The quantity and quality of postapproval clinical evidence varied substantially for novel drugs first approved by the FDA on the basis of limited evidence, with few controlled studies published after approval that confirmed efficacy using clinical outcomes for the original FDA approved indication.

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

“…The limited availability of studies showing either benefits to overall survival or quality of life in the postmarketing period underscores the importance of requiring robust evidence of clinical benefit at the time of marketing authorisation 9091 92 …”

“…The limited availability of studies showing either benefits to overall survival or quality of life in the postmarketing period underscores the importance of requiring robust evidence of clinical benefit at the time of marketing authorisation. [90][91][92] The EMA and other drug regulatory agencies should reconsider when, and to what extent, it is appropriate to approve new cancer drugs on the basis of surrogate endpoints. Furthermore, when gains in survival and quality of life are shown, these gains should be meaningful to patients and clinicians.…”

Postmarket studies required by the US Food and Drug Administration for new drugs and biologics approved between 2009 and 2012: cross sectional analysis

“…When postmarketing requirements did not specify a primary endpoint, we recorded the primary endpoint and corresponding duration provided in the ClinicalTrials.gov registration. Each primary endpoint was then classified as either a clinical outcome, clinical scale, surrogate outcome, or safety and tolerability outcome based on conventions used in previous research 13…”

“…However, over the past decade, the FDA has increasingly approved new drugs and biologics on the basis of shorter, smaller, and fewer trials 1. This shift corresponds with the FDA’s adoption of a lifecycle evaluation process, which emphasizes the importance of continued evaluation and monitoring of safety and effectiveness in the postmarket period 2345. Reflecting this emphasis, the FDA can use four separate authorities to require drug sponsors to conduct studies after approval to answer important questions about the benefits, harms, and optimal uses of new drugs and biologics (that is, postmarketing requirements, table 1).…”

New agreement on branded drugs for the NHS

“…Faster track appraisal by NICE risks basing funding and therapeutic decisions on incomplete data. There are few incentives for companies to evaluate their products rigorously after faster regulatory appraisals 34. And even when fast track approvals are conditional on subsequent evaluations, as happens through the Cancer Drugs Fund, the reliance on non-randomised studies to evaluate effectiveness in practice has been criticised 5.…”